Conventional chemotherapy can effectively treat the symptom of cancer initially, but its efficacy is often compromised by late tumor relapse. Many chemotherapeutic agents are shown to have immunostimulatory effects, and these findings drive a growing interest in combining chemotherapy and immunotherapy for synergistic antitumor effects and improved clinical outcomes. The goal of this project is to understand how antitumor CD4 effector T cells can be utilized to activate host immunity and prevent tumor re-growth after chemotherapy. Our central hypothesis is that successful tumor eradication after chemotherapy is attainable only if highly activated polyfunctional CD4 effector T cells can be created and maintained. The significance of the study is that it identifies antitumor CD4 effector T cells as a key gatekeeper of the overall host immunity, whose functional status (polyfunctional vs. tolerized) fundamentally drives the choice between eradication versus re-growth of residual tumors. The proposed project focuses on developing strategies to induce and maintain polyfunctional CD4 effector T cells in the post-chemotherapy immune milieu, and sustain the productive engagement of these cells with other immune cells to mount durable antitumor responses. We will attain these objectives by pursuing three highly-integrated specific aims. In aim 1, we will elucidate how type I IFN activates antigen-presenting cells, and acts in concert with IL7 to confer polyfunctional effector properties to CD4 T cells in the post-chemotherapy window. In aim 2, we will investigate the mechanisms of action of antitumor CD4 effector T cells in modifying the tumor milieu and driving effective CD8 responses. We will also elucidate the intrinsic (PD1) and extrinsic (Treg) inhibitory mechanisms that limit the durable effectiveness of CD4 effector T cells. In aim 3, we will translate the mechanistic insights from aims 1 and 2 into a combinatorial therapeutic strategy that targets mutually-reinforcing immune pathways, including CD40 ligation, PD1 blockade and provision of exogenous IL7, all of which converge to achieve a durable polyfunctional CD4 response and lasting antitumor immunity. Successful completion of this project will provide mechanistic basis for the design and implementation of effective combination chemoimmunotherapies for various cancers.